Acyclovir diester derivatives

Abstract

Disclosed are novel prodrugs represented by the following structural formula: Z is oxygen or sulfur; Y is, together with a hydroxy group, acyclovir or an analog of acyclovir; A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphate ester, which can be converted in vivo to a hydroxy or amino group. Also disclosed is a method of treating a viral infection in an individual or animal. The method comprises administering to the individual or animal a therapeutically effective amount of a prodrug represented by structural formula shown above.

What is claimed is:  
     
         1 . A prodrug of acyclovir or an acyclovir analog represented by a structural formula selected from the group consisting of:  
                   and physiologically acceptable salts thereof;    wherein Z is oxygen or sulfur;    Y, together with a hydroxy group, is acyclovir or an acyclovir analog; and    A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphoester, which can be converted in vivo to a hydroxy or amino group.    
     
     
         2 . The prodrug of    claim 1    wherein Y is represented by the following structural formula:  
                 

 and physiologically acceptable salts thereof;  
 wherein: 
 X is sulphur, —NH—, —N(lower alkyl)- or oxygen;  
 R a  is hydrogen, halogen, hydroxy, (lower alkyl)—O—, azide, thio, (lower alkyl)thio, amino, (lower alkyl)amino or di(lower alkyl)amino;  
 R b  is hydrogen, halogen, (lower alkyl)thio, (lower alkyl) —CO—NH—, amino or azide;  
 R c  is hydrogen, lower alkyl, substituted lower alkyl, aryl and substituted aryl;  
 R d  is hydrogen or lower alkyl;  
 R e  is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, (lower alkyl)O—, (substituted lower alkyl)O—, aryloxy and substituted aryloxy; and  
 A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphoester, which can be converted in vivo to a hydroxy or amino group.  
 
 
     
     
         3 . The prodrug of    claim 2    wherein Z and X are oxygen, R a  is —OH and R b  is —NH 2 .  
     
     
         4 . The prodrug of    claim 3    wherein R c , R d  and R e  are each —H.  
     
     
         5 . The prodrug of    claim 4    wherein the one or more groups in the para or ortho positions of A relative to the phosphoester are selected from the group consisting of R 8 —O—CO—O—, R 8 NH—CC—O—, and R 8 CO—O—, wherein R 8  is selected from the group consisting of lower alkyl, substituted lower alkyl, aryl and substituted aryl.  
     
     
         6 . The prodrug of    claim 5    wherein the benzyl group is α-substituted with a moiety such that cleavage of the phosphoester bond between A and a phosphate oxygen results in an elimination reaction to form a carbon-carbon double bond between the α-carbon and the moiety.  
     
     
         7 . The prodrug of    claim 5    wherein the one or more groups in the para or ortho positions relative to the phosphoester are (lower alkyl)CO—O—.  
     
     
         8 . The prodrug of    claim 4    wherein A is represented by the following structural formula:  
                 

 wherein:  
 R 1 , R 3 , or R 6  are independently selected from the group consisting of —H, —O—CO—R 8 , —O—CO—OR 8 , —O—C(O)—NHR 8 , —O—C(O)—N(R 8 ) 2 , —NH—CO—R 8 , —NH—CO—OR 8 , —NH—CO—NHR 8  and an inert group, with the proviso that at least one of R 1 , R 3  or R 6 , is not an inert group;  
 R 2  and R 7  are hydrogen, —O—CO—R 8 , or an inert group and may be the same or different;  
 R 4  and R 5  are independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group and a moiety such that cleavage of the phosphoester bond between A and a phosphate oxygen results in an elimination reaction to form a carbon-carbon double bond between the benzylic position of A and the moiety; and  
 R 8  is selected from the group consisting of a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, and a group such that the resulting ester, carbonate, amide, carbamate or urea moiety is degraded to the free phenolic hydroxy group or free amine group in vivo.  
 
     
     
         9 . The prodrug of    claim 8    wherein at least one of R 1 , R 3  or R 6  is a (—O—CO—R 8 ) group.  
     
     
         10 . The prodrug of    claim 9    wherein R 4  is selected from the group consisting —CH 2 COOR″, —CH 2 COR″, —CH 2 CONH 2 , —CH 2 CONHR″, —CH 2 NO 2 , —CH 2 SO 2 R″ and —CH 2 CN, wherein R″ is selected from the group consisting of lower alkyl, substituted lower alkyl, aryl and substituted aryl.  
     
     
         11 . The prodrug of    claim 10    wherein R 4  is a —CH 2 —CO 2 —R″.  
     
     
         12 . The prodrug of    claim 11    wherein R″ is selected from the group consisting of —H, methyl, ethyl, n-propyl, iso-isopropyl, n-butyl, sec-butyl, t-butyl or —(CH 2 ) n CH 3 , wherein n is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.  
     
     
         13 . The prodrug of    claim 12    wherein R 1  is a —O—CO—R 8 .  
     
     
         14 . The prodrug of    claim 13    wherein R 8  is selected from the group consisting of methyl, ethyl n-propyl, iso-isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, CH 3 —CO—CH 2 —, CH 3 O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—CH 2 —, CH 3 O—(CH 2 ) 2 —O—CH 2 —, —OCH 3 , —CR 9 —NHR 10 , —CH(OR 11 )—CH 3  and —CH 2 OR 11 ; 
 wherein:  
 R 9  is the side chain of an amino acid;  
 R 10  is —H or an amine protecting group; and  
 R 11  is —H or an alcohol protecting group.  
 
     
     
         15 . A prodrug represented by the following structural formula:  
                   and physiologically acceptable salts thereof.    
     
     
         16 . A prodrug represented by the following structural formula:  
                   and physiologically acceptable salts thereof.    
     
     
         17 . A method of treating an individual with a viral infection, comprising administering to the individual a therapeutically effective amount of a prodrug represented by the following structural formula:  
                   and physiologically acceptable salts thereof;    wherein Z is oxygen or sulfur;    Y is, together with a hydroxy group, acyclovir or an acyclovir analog; and    A is a substituted benzyl derivative with one or more protected phenol or protected amine groups in the ortho or para positions, relative to the phosphoester, which can be converted in vivo to a hydroxy or amino group.    
     
     
         18 . The method of    claim 17    wherein Y is represented by the following structural formula:  
                 

 and physiologically acceptable salts thereof;  
 wherein:  
 X is sulphur, —NH—, —N(lower alkyl)- or oxygen;  
 R a  is hydrogen, halogen, hydroxy, (lower alkyl)—O—, azide, thio, (lower alkyl)thio, amino, (lower alkyl) amino or di(lower alkyl)amino;  
 R b  is hydrogen, halogen, (lower alkyl)thio, (lower alkyl)—CO—NH—, amino or azide;  
 R c  is hydrogen, lower alkyl, substituted lower alkyl, aryl and substituted aryl;  
 R d  is hydrogen or lower alkyl;  
 R e  is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, (lower alkyl)O—, (substituted lower alkyl)O—, aryloxy and substituted aryloxy; and  
 A is a substituted benzyl derivative with one or more protected phenol or protected amine groups in the ortho or para positions, relative to the phosphoester, which can be converted in vivo to a hydroxy or amino group.  
 
     
     
         19 . The method of    claim 18    wherein the viral infection is caused by Herpes Simplex Virus.  
     
     
         20 . The method of    claim 19    wherein the viral infection is a dermal viral infection.  
     
     
         21 . The method of    claim 20    wherein the prodrug is administered topically to the dermal viral infection.  
     
     
         22 . The method of    claim 21    wherein Z and X are oxygen, R a  is —OH and R b  is —NH 2 .  
     
     
         23 . The method of    claim 22    wherein R c , R d  and R e  are each —H.  
     
     
         24 . The method of    claim 23    wherein the one or more groups in the para or ortho positions of A relative to the phosphoester are selected from the group consisting of R 8 —O—CO—O—, R 8 NH—CO—O—, and R 8 CO—O—, wherein R 8  is selected from the group consisting of lower alkyl, substituted lower alkyl, aryl, and substituted aryl.  
     
     
         25 . The method of    claim 24    wherein the benzyl group is α-substituted by a moiety such that cleavage of the phosphoester bond between A and a phosphate oxygen will result in an elimination reaction to form a carbon-carbon double bond between the α-carbon and the moiety.  
     
     
         26 . The method of    claim 25    wherein the one or more groups in the para or ortho positions relative to the phosphoester are (lower alkyl)CO—O—.  
     
     
         27 . The method of    claim 23    wherein A is of the formula:  
                 

 wherein:  
 R 1 , R 3  or R 6  are independently selected from the group consisting of —H, —O—CO—R 8 , —O—CO—OR 8 , —O—C(O)—NHR 8 , —O—C(O)—N(R 8 ) 2 , —NH—CO—R 8 , —NH—CO—OR 8 , —NH—CO—NHR 8  and an inert group, with the proviso that at least one of R 1 , R 3  or R 6  is not an inert group;  
 R 2  and R 7  are hydrogen —O—CO—R 8 , or an inert group and may be the same or different;  
 R 4  and R 5  are independently selected from the group consisting of hydrogen, an alkyl group, a substituted alkyl group and a moiety such that cleavage of the phosphoester bond between A and a phosphate oxygen results in an elimination reaction to form a carbon-carbon double bond between the benzylic position of A and the moiety; and  
 R 8  is selected from the group consisting of an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, and a group such that the resulting ester, carbonate, amide, carbamate or urea moiety is degraded to the free hydroxy group or free amine group in vivo.  
 
     
     
         28 . The method of    claim 27    wherein at least one of R 1 , R 3  or R 6  is a (—O—CO—R 8 ) group.  
     
     
         29 . The method of    claim 28    wherein R 4  is selected from the group consisting of —CH 2 COOR″, —CH 2 COR″, —CH 2 CONH 2 , —CH 2 CONHR″, —CH 2 NO 2 , —CH 2 SO 2 R″ and —CH 2 CN, wherein R″ is selected from the group consisting of —H, lower alkyl, substituted lower alkyl, aryl and substituted aryl.  
     
     
         30 . The method of    claim 29    wherein R 4  is a (—CH 2 —CO 2 —R″) group.  
     
     
         31 . The method of    claim 30    wherein R″ is selected from the group consisting of —H, methyl, ethyl, n-propyl, iso-isopropyl, n-butyl, sec-butyl, t-butyl or —(CH 2 ) n CH 3 , wherein n is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.  
     
     
         32 . The method of    claim 31    wherein R 1  is a (—O—CO—R 8 ) group.  
     
     
         33 . The method of    claim 32    wherein R 8  is selected from the group consisting of methyl, ethyl n-propyl, iso-isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, CH 3 —CO—CH 2 —, CH 3 O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—CH 2 —, CH 3 O—(CH 2 ) 2 —O—CH 2 —, —OCH 3 —CR 9 —NHR 10 , —CH(OR 11 )—CH 3  and —CH 2 OR 11 ; 
 wherein:  
 R 9  is the side chain of an amino acid;  
 R 10  is —H or an amine protecting group; and  
 R 11  is —H or an alcohol protecting group.  
 
     
     
         34 . A method of treating an individual or animal with a viral infection, comprising administering to the individual a therapeutically effective amount of a prodrug represented by the following structural formula:  
                   and physiologically acceptable salts thereof.    
     
     
         35 . A method of treating an individual or animal with a viral infection, comprising administering to the individual a therapeutically effective amount of a prodrug represented by the following structural formula:  
                   and physiologically acceptable salts thereof.    
     
     
         36 . A method of preparing a compound represented by the following structural formula:  
                   wherein:    Y′ is, together with a hydroxy group, a nucleoside analog; and    A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphite ester which can be converted in vivo to a hydroxy or amino group;    comprising reacting Y′—OH, a weak anhydrous organic acid and (A—O) 2 —P(NR 21 R 22 ) in an aprotic polar organic solvent, wherein R 21  and R 22  are each independently a lower alkyl, a substituted lower alkyl group, an aryl group, a substituted aryl group or, taken together with the phosphoramide nitrogen, are a substituted or unsubstituted five, six or seven membered nitrogen-containing heterocyclic ring.    
     
     
         37 . A method of preparing a compound represented by the following structural formula:  
                   wherein:    Y is, together with a hydroxy group, acyclovir or an analog of acyclovir; and    A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphite ester which can be converted in vivo to a hydroxy or amino group;    comprising reacting Y—OH, H-tetrazole and (A—O) 2 — P(NR 21 R 22 ) in an aprotic polar organic solvent, wherein R 21  and R 22  are each independently a lower alkyl, substituted lower alkyl group, an aryl group a substituted aryl group or, taken together with the phosphoramide nitrogen, are a substituted or unsubstituted five, six or seven membered nitrogen-containing heterocyclic ring.    
     
     
         38 . The method of    claim 37    wherein A is represented by the following structural formula:  
                 

 wherein R 4  is —CH 2 COOCH 3  and R 8  is methyl or t-butyl.  
 
     
     
         39 . The method of    claim 38    wherein the aprotic polar solvent is dimethylformamide and R 21  and R 22  are each ethyl.  
     
     
         40 . A method of preparing a prodrug represented by the following structural formula:  
                   wherein:    Y is, together with a hydroxy group, acyclovir or an analog of acyclovir; and    A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphite ester which can be converted in vivo to a hydroxy or amino group;    comprising the steps of: 
 a) reacting Y—OH, H-tetrazole and (A—O) 2 —P(NR 21 R 22 )in an aprotic polar solvent, wherein R 21  and R 22  are each independently a lower alkyl, a substituted lower alkyl group, an aryl group, a substituted aryl group or, taken together with the phosphoramide nitrogen, are a substituted or unsubstituted five, six or seven membered nitrogen-containing heterocyclic ring,  
   thereby producing an intermediate represented by the following structural formula:  
                 

 b) reacting the intermediate with hydrogen peroxide thereby forming the prodrug.  
   
     
     
         41 . The method of    claim 40    wherein A is represented by the following structural formula:  
                 

 wherein R 4  is —CH 2 COOCH 3  and R 8  is methyl or t-butyl.  
 
     
     
         42 . The method of    claim 41    wherein the aprotic polar is dimethylformamide, R 21  and R 22  are each ethyl and step b) is performed without isolating the intermediate.  
     
     
         43 . A method of preparing a prodrug represented by the following structural formula:  
                   wherein:    Y is, together with a hydroxy group, acyclovir or an analog of acyclovir;    A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphate ester which can be converted in vivo to a hydroxy or amino group;    comprising the steps of: 
 a) reacting Y—OH, a weak anhydrous organic acid and (A—O) 2 —P(NR 21 R 22 ) in an aprotic polar solvent, wherein R 21  and R 22  are each independently a lower alkyl, substituted lower alkyl group, an aryl group, a substituted aryl group or, taken together with the phosphoramide nitrogen, are a substituted or unsubstituted five, six or seven membered nitrogen-containing heterocyclic ring, thereby producing a first intermediate represented by the following structural formula:  
                 
 
 b) reacting the first intermediate with a phosphite oxidizing agent, thereby forming a second intermediate represented by the following structural formula:  
                 
 
 c) reacting the second intermediate with a base to form the prodrug.  
   
     
     
         44 . The method of    claim 43    wherein A is represented by the following structural formula:  
                 

 wherein:  
 R 8  is selected from the group consisting of methyl, ethyl, n-propyl, iso-isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, CH 3 —CO—CH 2 —, CH 3 O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—CH 2 —, CH 3 O—(CH 2 ) 2 —O—CH 2 — and —OCH 3 ; and  
 R″ is selected from the group consisting of —H, methyl, ethyl n-propyl, iso-isopropyl, n-butyl, sec-butyl, t-butyl.  
 
     
     
         45 . The method of    claim 44    wherein: 
 a) R 4  is —CH 2 CCOR″;  
 b) R 8  is methyl or t-butyl;  
 c) the aprotic dipolar solvent is a dialkyl amide solvent;  
 d) R 21  and R 22  are each ethyl; and  
 e) the weak anhydrous organic base acid is H-tetrazole.  
 
     
     
         46 . The method of    claim 45    wherein the base an amine base and the dialkylamide solvent is dimethylformamide.  
     
     
         47 . A method of preparing a prodrug represented by the following structural formula:  
                   wherein:    Y is, together with a hydroxy group, acyclovir or an analog of acyclovir;    A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphate ester which can be converted in vivo to a hydroxy or amino group;    said method comprising the step of reacting a base with a compound represented by the following structural formula:  
                 
   thereby forming the prodrug.    
     
     
         48 . The method of    claim 46    wherein A is represented by the following structural formula:  
                 

 wherein:  
 R 8  is selected from the group consisting of methyl, ethyl, n-propyl, iso-isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, CH 3 —CO—CH 2 ,—, CH 3 O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—CH 2 —, CH 3 O—(CH 2 ) 2 O—CH 2 — and —OCH 3 ; and  
 R″ is selected from the group consisting of —H, methyl, ethyl n-propyl, iso-isopropyl, n-butyl, sec-butyl, t-butyl.  
 
     
     
         49 . The method of    claim 48    wherein: 
 a) R 4  is —CH 2 COOR″;  
 b) R 8  is methyl or t-butyl; and  
 c) R 21  and R 22  are each ethyl.  
 
     
     
         50 . The method of    claim 49    wherein the base is an amine base.  
     
     
         51 . A method of preparing a prodrug represented by the following structural formula:  
                   wherein:    Y′ is, together with a hydroxy group, a nucleoside analog;    A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphate ester which can be converted in vivo to a hydroxy or amino group;    said method comprising the step of reacting a base with a compound represented by the following structural formula:  
                 
   thereby forming the prodrug.