Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same

A diastereomerically enriched compound having the structure (3)

• 35
• which is substantially free of the diastereomer (4)
• 36
• wherein
• R1 is an oxyester which is hydrolyzable in vivo, or hydroxyl;
• B is a heterocyclic base;
• R2 is hydroxyl, or the residue of an amino acid bonded to the P atom through an amino group of the amino acid and having each carboxy substituent of the amino acid optionally esterified, but not both of R1 and R2 are hydroxyl;
• E is —(CH2)2—, —CH(CH3)CH2—, —CH(CH2F)CH2—, —CH(CH2OH)CH2—, —CH (CH═CH2)CH2—, —CH(C≡CH)CH2—, —CH(CH2N3)CH2—,
• 37
• —CH(R6)OCH(R6′)—, —CH(R9)CH2O— or —CH(R8)O—, wherein the right hand bond is linked to the heterocyclic base;
• the broken line represents an optional double bond;
• R4 and R5 are independently hydrogen, hydroxy, halo, amino or a substituent having 1-5 carbon atoms selected from acyloxy, alkyoxy, alkylthio, alkylamino and dialkylamino;
• R6 and R6′ are independently H, C1-C6 alkyl C1-C6hydroxyalkyl, or C2-C7 alkanoyl;
• R7 is independently H, C1-C6 alkyl, or are taken together to form —O— or —CH2—;
• R8 is H, C1-C6 alkyl, C1-C6 hydroxyalkyl or C1-C6 haloalkyl;
• and
• R9 is H, hydroxymethyl or acyloxymethyl;
• and their salts, free base, and solvates.

A diastereomerically enriched compound having the structure (5a)

• 38
• which is substantially free of diastereomer (5b)
• 39
• wherein
• R5 is methyl or hydrogen;
• R6 independently is H, alkyl, alkenyl, alkynyl, aryl or arylalkyl, or R6 independently is alkyl, alkenyl, alkynyl, aryl or arylalkyl which is substituted with from 1 to 3 substituents selected from alkylamino, alkylaminoalkyl, dialkylaminoalkyl, dialkylamino, hydroxyl, oxo, halo, amino, alkylthio, alkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylalkoxyalkyl, haloalkyl, nitro, nitroalkyl, azido, azidoalkyl, alkylacyl, alkylacylalkyl, carboxyl, or alkylacylamino;
• R7 is the side chain of any naturally-occurring or pharmaceutically acceptable amino acid and which, if the side chain comprises carboxyl, the carboxyl group is optionally esterified with an alkyl or aryl group;
• R11 is amino, alkylamino, oxo, or dialkylamino;
• and
• R12 is amino or H;
• and it salts, tautomers, free base and solvates.