Acyclovir diester derivatives

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:

• 19
• 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.

A method of preparing a compound represented by the following structural formula:

• 24
• 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(NR21R22) in an aprotic polar organic solvent, wherein R21 and R22 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.

A method of preparing a compound represented by the following structural formula:

• 25
• 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(NR21R22) in an aprotic polar organic solvent, wherein R21 and R22 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.

A method of preparing a prodrug represented by the following structural formula:

• 27
• 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(NR21R22)in an aprotic polar solvent, wherein R21 and R22 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:
• 28
• b) reacting the intermediate with hydrogen peroxide thereby forming the prodrug.

A method of preparing a prodrug represented by the following structural formula:

• 30
• 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(NR21R22) in an aprotic polar solvent, wherein R21 and R22 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:
• 31
• b) reacting the first intermediate with a phosphite oxidizing agent, thereby forming a second intermediate represented by the following structural formula:
• 32
• c) reacting the second intermediate with a base to form the prodrug.

A method of preparing a prodrug represented by the following structural formula:

• 34
• 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:
• 35
• thereby forming the prodrug.

A method of preparing a prodrug represented by the following structural formula:

• 37
• 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:
• 38
• thereby forming the prodrug.