Phosphonyl ester conjugates as prodrugs
Cidofovir or foscarnet based compounds having an amino acid or dipeptide esters are provided as prodrugs.
1. A prodrug compound
where Nt is
Q is O or S; R 3 is —(CH 2 ) n —, —CHCH 3 (CH 2 ) n —, or —(C 6 H 4 )(CH 2 ) n ; R 4 is O-isopropyl, O-isobutyl, O-tert-butyl, O-2-tert-pentyl, —O—(CH 2 ) n —C 6 R 5 10 , —O—(CH 2 ) n —CH—(C 6 R 5 10 ) 2 , —O—(CH 2 ) n C(C 6 R 5 10 ) 3 , or —O—C 5 N′R 5 10 ; n is independently in each occurrence an integer between 0 and 12; R 10 is independently in each occurrence H, F, Cl, Br, C 1 -C 4 alkyl, C 0 -C 4 primary amine, C 0 -C 4 amine having one or two C 1 -C 8 alkyl substituents, C 0 -C 4 hydroxyl, C 0 -C 4 carboxyl, C 0 -C 4 sulfonate, and a quaternary amine or
R 5 is H, or
R 6 is an amino acid side chain of —H, —NH 2 , —C 1-5 alkyl, —C 1-5 alkanol, —C 1-5 alkyl carboxylic acid, —C 1-5 alkyl amine, —C 1-5 alkyl amide, —C 1-5 alkyl imine, —C 1-5 alkyl delta-guanido and -methylphenyl; and R 7 is —O-isopropyl, —O-isobutyl, —O-tert-butyl, —O-isopentyl or —O-2-tert-pentyl; C* is either a R- or S-chiral carbon atom; and L is a nullity or a linker a group of C 1 -C 8 alkyl, C 1 -C 8 alkyl having a pendent heteroatom containing moiety of O, N or S present as a carboxyl, carbonyl, hydroxyl, amino, amido, sulfonyl, or quaternary amino.
2. A prodrug compound
where Nt is
Q is O or S; R 3 is —CH 2 —, R 4 is O-isopropyl; R 5 is
R 6 is —CH(CH 3 ) 2 ; L is a nullity; n is independently in each occurrence an integer between 0 and 12; R 10 is independently in each occurrence H, F, Cl, Br, C 1 -C 4 alkyl, C 0 -C 4 primary amine, C 0 -C 4 amine having one or two C 1 -C 8 alkyl substituents, C 0 -C 4 hydroxyl, C 0 -C 4 carboxyl, C 0 -C 4 sulfonate, and a quaternary amine or
R 5 is H, or
R 6 is an amino acid side chain of —H, —NH 2 , —C 1-5 alkyl, —C 1-5 alkanol, —C 1-5 alkyl carboxylic acid, —C 1-5 alkyl amine, —C 1-5 alkyl amide, —C 1-5 alkyl imine, —C 1-5 alkyl delta-guanido and -methylphenyl; and R 7 is —O-isopropyl, —O-isobutyl, —O-tert-butyl, —O-isopentyl or —O-2-tert-pentyl; C* is either a R- or S-chiral carbon atom.
3. The compound of claim 2 wherein C* is a R-chiral carbon atom.
4. The compound of claim 1 wherein Nt is
and R 4 is —O—CH 2 —C 6 H 5 or —O—(CH 2 )—C 6 H 4 R 10 with the proviso R 10 is not H.
5. A cidofovir compound having the structure of various valine-serine isopropyl esters of cidofovir and various threonine esters of cyclic cidofovir.