Method to improve antiviral activity of nucleotide analogue drugs
An amino acid conjugate of a cyclic or acyclic nucleoside phosphonate is provided. In some cases, the amino acid conjugate is a tyrosine alkyl amide phosphonate ester conjugate of a cyclic or acyclic nucleoside phosphonate, and is useful as an antiviral compound. In certain cases, the tyrosine conjugate includes a long chain alkyl group on the carboxamide group of the tyrosine residue. In a method of preparing an acyclic tyrosine conjugate, a tert-butyloxycarbonyl (Boc) protected tyrosine residue containing a long chain alkyl group is reacted with an acyclic nucleoside phosphonate mono-ethyl ester in the presence of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate to produce a Boc-protected nucleoside phosphonate di-ester, and the di-ester is deethylated and deprotected to produce the tyrosine conjugate. Methods of inhibiting viral replication and methods of treating a viral infection using the amino acid conjugate are also provided.
1. A compound of the following formula (I) or (II), or a pharmaceutically acceptable salt thereof:
wherein B is 9 adeninyl, 1-cytosinyl, 9-guaninyl, 2,6-diamino-9-purinyl, 7-deaza-9-guaninyl, 8-aza-9-guaninyl or 2,4-diaminopyrimidine-6-oxidanyl, R is H, CH 2 OH or methyl, and R 2 is a C 12-18 alkyl group.
2. The compound of claim 1 , wherein R 2 is a C 14-18 alkyl group.
3. The compound of claim 1 , wherein R 2 is a C 16 alkyl group.
4. A compound of claim 1 , wherein the compound is:
O-[(5S)-5-[(6-Amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-dodecyl-(L)-tyrosinamide ((L)-Tyr(NHC 12 H 25 )—(S)-cHPMPA),
O-[(5S)-5-[(6-Amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-tetradecyl-(L)-tyrosinamide ((L)-Tyr (NHC 14 H 29 )—(S)-cHPMPA),
O-[(5S)-5-[(6-Amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-hexadecyl-(L)-tyrosinamide ((L)-Tyr (NHC 16 H 33 )—(S)-cHPMPA),
O-[(5S)-5-[(6-Amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-octadecyl-(L)-tyrosinamide ((L)-Tyr(NHC 18 H 37 )—(S)-cHPMPA),
O-[([[(2S)-1-(6-Amino-9H-purin-9-yl)-3-hydroxypropan-2-yl]oxy]methyl)(hydroxy)-phosphoryl]-N-dodecyl-(L)-tyrosinamide ((L)-Tyr (NHC 12 H 25 )—(S)-HPMPA),
O-[([[(2S)-1-(6-Amino-9H-purin-9-yl)-3-hydroxypropan-2-yl]oxy]methyl)(hydroxy)-phosphoryl]-N-tetradecyl-(L)-tyrosinamide ((L)-Tyr (NHC 14 H 29 )—(S)-HPMPA),
O-[([[(2S)-1-(6-Amino-9H-purin-9-yl)-3-hydroxypropan-2-yl]oxy]methyl)(hydroxy)-phosphoryl]-N-hexadecyl-(L)-tyrosinamide ((L)-Tyr (NHC 16 H 33 )—(S)-HPMPA),
O-[([[(2S)-1-(6-Amino-9H-purin-9-yl)-3-hydroxypropan-2-yl]oxy]methyl)-(hydroxy)-phosphoryl]-N-octadecyl-(L)-tyrosinamide ((L)-Tyr (NHC 18 H 37 )—(S)-HPMPA),
O-[(5S)-5-[(4-amino-2-oxopyrimidin-1 (2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-hexadecyl-(L)-tyrosinamide ((L)-Tyr (NHC 16 H 33 )—(S)-cHPMPC);
O-[([[(2S)-1-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxypropan-2-yl] oxy]methyl)-(hydroxy)phosphoryl]-N-hexadecyl-(L)-tyrosinamide ((L)-Tyr (NHC 16 H 33 )—(S)-HPMPC), or
O-[{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}(hydroxy)phosphoryl]-N-hexadecyl-L-tyrosinamide ((L)-Tyr (NHC 16 H 33 )-PMEA).
5. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5 , wherein R 2 is C 14-18 alkyl group.
7. The pharmaceutical composition of claim 5 , wherein the compound is
(L)-Tyr(NHC 12 H 25 )—(S)-cHPMPA,
(L)-Tyr(NHC 14 H 29 )—(S)-cHPMPA,
(L)-Tyr(NHC 16 H 33 )—(S)-cHPMPA,
(L)-Tyr(NHC 18 H 37 )—(S)-cHPMPA,
(L)-Tyr(NHC 12 H 25 )—(S)-HPMPA,
(L)-Tyr(NHC 14 H 29 )—(S)-HPMPA,
(L)-Tyr(NHC 16 H 33 )—(S)-HPMPA,
(L)-Tyr(NHC 18 H 37 )—(S)-HPMPA,
((L)-Tyr(NHC 16 H 33 )—(S)-cHPMPC,
((L)-Tyr(NHC 16 H 33 )—(S)-HPMPC, or
(L)-Tyr (NHC 16 H 33 )-PMEA.
8. The pharmaceutical composition of claim 5 , wherein R 2 is a C 16 alkyl group.
9. A method of inhibiting viral replication in a pox or herpes virus-infected cell in need thereof, comprising exposing the cell in culture to a compound of claim 1 .
10. The method of claim 9 , wherein R 2 is C 14-18 alkyl group.
11. The method of claim 9 , wherein the compound is
(L)-Tyr(NHC 12 H 25 )—(S)-cHPMPA,
(L)-Tyr(NHC 14 H 29 )—(S)-cHPMPA,
(L)-Tyr(NHC 16 H 33 )—(S)-cHPMPA,
(L)-Tyr(NHC 18 H 37 )—(S)-cHPMPA,
(L)-Tyr(NHC 12 H 25 )—(S)-HPMPA,
(L)-Tyr(NHC 14 H 29 )—(S)-HPMPA,
(L)-Tyr(NHC 16 H 33 )—(S)-HPMPA,
(L)-Tyr(NHC 18 H 37 )—(S)-HPMPA,
((L)-Tyr (NHC 16 H 33 )—(S)-cHPMPC,
((L)-Tyr(NHC 16 H 33 )—(S)-HPMPC, or
(L)-Tyr (NHC 16 H 33 )-PMEA.
12. The method of claim 9 , wherein R 2 is a C 16 alkyl group.
13. A method of treating a pox or herpes virus infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of claim 1 .
14. The method of claim 13 , wherein R 2 is C 14-18 alkyl group.
15. The method of claim 13 , wherein the compound is
(L)-Tyr(NHC 12 H 25 )—(S)-cHPMPA,
(L)-Tyr(NHC 14 H 29 )—(S)-cHPMPA,
(L)-Tyr(NHC 16 H 33 )—(S)-cHPMPA,
(L)-Tyr(NHC 18 H 37 )—(S)-cHPMPA,
(L)-Tyr(NHC 12 H 25 )—(S)-HPMPA,
(L)-Tyr(NHC 14 H 29 )—(S)-HPMPA,
(L)-Tyr(NHC 16 H 33 )—(S)-HPMPA,
(L)-Tyr(NHC 18 H 37 )—(S)-HPMPA,
((L)-Tyr(NHC 16 H 33 )—(S)-cHPMPC,
((L)-Tyr(NHC 16 H 33 )—(S)-HPMPC, or
(L)-Tyr (NHC 16 H 33 )-PMEA.
16. The method of claim 13 , wherein R 2 is a C 16 alkyl group.
17. A method of preparing an amino acid conjugate of an acyclic nucleoside phosphonate, comprising
reacting an acyclic nucleoside phosphonate with EtOH in the presence of bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) to produce a nucleoside phosphonate mono-ethyl ester of the formula
wherein B is a base and R is H or methyl;
coupling the nucleoside phosphonate mono-ethyl ester to a Boc-protected amino acid, said Boc-protected amino acid comprising a carboxamide group containing a C 6-20 alkyl moiety, to produce a Boc-protected nucleoside phosphonate di-ester of the formula
wherein R 1 is NHC n H (2n+1) , wherein n=6-20; and
deethylating and deprotecting the Boc-protected nucleoside phosphonate di-ester to produce an acyclic nucleoside phosphonate analogue of the formula
wherein B is 9-adeninyl, 1-cytosinyl, 9-guaninyl, 2,6-diamino-9-purinyl, 7-deaza-9-guaninyl, 8-aza-9-guaninyl or 2,4-diaminopyrimidine-6-oxidanyl.
18. The method of claim 17 , wherein B is 9-adeninyl or 2,6-diamino-9-purinyl.