Claims for Patent: 5,922,695

Summary for Patent: 5,922,695

Title:	Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability
Abstract:	Novel compounds are provided that comprise esters of antiviral phosphonomethoxy nucleotide analogs with carbonates and/or carbamates having the structure --OC(R2)2 OC(O)X(R)a, wherein R2 independently is H, C1 -C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR3 in which R3 is C1 -C12 alkyl; X is N or O; R is independently H, C1 -C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro, --O--, --N═, --NR4 --, --N(R4)2 -- or OR3, R4 independently is --H or C1 -C8 alkyl, provided that at least one R is not H; and a is 1 or 2, with the proviso that when a is 2 and X is N, (a) two R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, or (b) one R additionally can be OR3. The compounds are useful as intermediates for the preparation of antiviral compounds or oligonucleotides, or are useful for administration directly to patients for antiviral therapy or prophylaxis. Embodiments are particularly useful when administered orally.
Inventor(s):	Murty N. Arimilli, Kenneth C. Cundy, Joseph P. Dougherty, Choung U. Kim, Reza Oliyai, Valentino J. Stella
Assignee:	Gilead Sciences Inc
Application Number:	US08/900,746
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 5,922,695
Patent Claims:	1. A compound having formula (1a) ##STR33## wherein Z is independently --OC(R2)2 OC(O)X(R)a, an ester, an amidate or --H, but at least one Z is --OC(R2)2 OC(O)X(R)a ;A is the residue of an antiviral phosphonomethoxy nucleotide analog; X is N or O; R2 independently is --H, C1 -C12 alkyl, C5 -C12 aryl, C2 -C12 alkenyl, C2 -C12 alkynyl, C7 -C12 alkenylaryl, C7 -C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or --OR3 in which R3 is C1 -C12 alkyl, C2 -C12 alkenyl, C2-C 12 alkynyl or C5 -C12 aryl; R is independently --H, C1 -C12 alkyl, C5 -C12 aryl, C2 -C12 alkenyl, C2 -C12 alkynyl, C7 -C12 alkyenylaryl, C7 -C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, --N(R4)2 or --OR3, where R4 independently is --H or C1 -C8 alkyl, provided that at least one R is not H; and a is 1 when X is O, or 1 or 2 when X is N; with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be --OR3 or (c) both N-linked R groups can be --H; and the salts, hydrates, tautomers and solvates thereof. 2. The compound of claim 1 having formula (1) ##STR34## wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;R is independently --H, C1 -C12 alkyl, C5 -C12 aryl, C2 -C12 alkenyl, C2 -C12 alkynyl, C7 -C12 alkenylaryl, C7 -C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or --OR3 in which R3 is C1 -C12 alkyl, C2 -C12 alkenyl, C2 -C12 alkynyl or C5 -C12 aryl; R1 is hydrogen, --CH3, --CH2 OH, --CH2 F, --CH═CH2, or --CH2 N3, or R1 and R8 are joined to form --CH2 --; R2 independently is hydrogen or C1 -C6 alkyl; and R8 is hydrogen or --CHR2 --O--C(O)--OR, or R8 is joined with R1 to form --CH2 --; and the salts, hydrates, tautomers and solvates thereof. 3. The compound of claim 2 wherein R2 is --H. 4. The compound of claim 3 wherein R1 is --CH3. 5. The compound of claim 1 wherein R2 is --H. 6. The compound of claim 1 wherein one R2 is --CH3 and the other R2 is H. 7. The compound of claim 1 wherein R3 is C1 -C6 alkyl or phenyl. 8. The compound of claim 1 wherein R3 is --CH3 or --C2 H5. 9. The compound of claim 1 wherein X is O. 10. The compound of claim 1 wherein X is N and one R3 is H. 11. The compound of claim 4 wherein the compound is enriched or resolved at the carbon atom chiral center linked to R1. 12. The compound of claim 4 wherein at least about 90% of the compound is in the (R) configuration at the R1 site. 13. The compound of claim 12 wherein B is adenin-9-yl. 14. The compound of claim 13 wherein each R is ethyl. 15. The compound of claim 13 wherein each R is isopropyl. 16. The compound of claim 13 wherein each R is 3-pentyl or neopentyl. 17. The compound of claim 13 wherein each R is t-butyl or isobutyl. 18. The compound of claim 4 wherein B is 2,6-diaminopurin-9-yl. 19. The compound of claim 3 wherein R1 is H. 20. The compound of claim 19 wherein B is adenin-9-yl. 21. The compound of claim 4 wherein R is C1 -C12 alkyl. 22. The compound of claim 3 wherein R1 is --CH2 OH. 23. The compound of claim 22 wherein B is cytosin-1-yl. 24. The compound of claim 22 wherein at least about 90% of the compound is in the (S) configuration at the R1 site. 25. A method comprising orally administering to a patient infected with virus or at risk to viral infection a therapeutically effective amount of a compound of claim 1. 26. A method for preparing a compound of formula (1a) of claim 1 comprising reacting the diacid of a phosphonomethoxy nucleotide analog with L--CH(R2)OC(O)X(R)n wherein L is a leaving group. 27. A method for preparing a compound of formula (1) of claim 2 comprising reacting a compound of formula (6) ##STR35## with L--CHR2 --O--C(O)--OR and recovering a compound of formula (1), wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;R1 is hydrogen, --CH3, --CH2 OH, --CH2 F, --CH═CH2, --CH2 N3 or R1 and R8 are joined to form --CH2 --; and R8 is hydrogen, --CHR2 --O--C(O)--OR or R8 is joined with R1 to form --CH2 --; and R2 is H, C1 -C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR3 in which R3 is C1 -C12 alkyl; R is independently H, C1 -C12 alkyl, aryl, alkenyl, alkynyl, alkenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR3, provided that at least one R is not H; and L is a leaving group. 28. The method of claim 27 comprising conducting the reaction using at least about 1.0 equivalent of L--CHR2 --O--C(O)--OR. 29. The method of claim 27 comprising conducting the reaction in the presence of an organic base in an organic solvent at a reaction temperature of about 4-100° C. for about 4-72 hours. 30. The method of claim 27 wherein the compound of formula (1) is recovered by forming a salt, precipitating the salt and recovering the precipitated salt. 31. The method of claim 30 wherein the salt is formed from sulfuric acid, phosphoric acid, lactic acid, or citric acid. 1. A compound having formula (1a) ##STR33## wherein Z is independently --OC(R.sup.2).sub.2 OC(O)X(R).sub.a, an ester, an amidate or --H, but at least one Z is --OC(R.sup.2).sub.2 OC(O)X(R).sub.a ; A is the residue of an antiviral phosphonomethoxy nucleotide analog; X is N or O; R.sup.2 independently is --H, C.sub.1 -C.sub.12 alkyl, C.sub.5 -C.sub.12 aryl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.7 -C.sub.12 alkenylaryl, C.sub.7 -C.sub.12 alkynylaryl, or C.sub.6 -C.sub.12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or --OR.sup.3 in which R.sup.3 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl or C.sub.5 -C.sub.12 aryl; R is independently --H, C.sub.1 -C.sub.12 alkyl, C.sub.5 -C.sub.12 aryl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.7 -C.sub.12 alkyenylaryl, C.sub.7 -C.sub.12 alkynylaryl, or C.sub.6 -C.sub.12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, --N(R.sup.4).sub.2 or --OR.sup.3, where R.sup.4 independently is --H or C.sub.1 -C.sub.8 alkyl, provided that at least one R is not H; and a is 1 when X is O, or 1 or 2 when X is N; with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be --OR.sup.3 or (c) both N-linked R groups can be --H; and the salts, hydrates, tautomers and solvates thereof. 2. The compound of claim 1 having formula (1) ##STR34## wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl; R is independently --H, C.sub.1 -C.sub.12 alkyl, C.sub.5 -C.sub.12 aryl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.7 -C.sub.12 alkenylaryl, C.sub.7 -C.sub.12 alkynylaryl, or C.sub.6 -C.sub.12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or --OR.sup.3 in which R.sup.3 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl or C.sub.5 -C.sub.12 aryl; R.sup.1 is hydrogen, --CH.sub.3, --CH.sub.2 OH, --CH.sub.2 F, --CH.dbd.CH.sub.2, or --CH.sub.2 N.sub.3, or R.sup.1 and R.sup.8 are joined to form --CH.sub.2 --; R.sup.2 independently is hydrogen or C.sub.1 -C.sub.6 alkyl; and R.sup.8 is hydrogen or --CHR.sup.2 --O--C(O)--OR, or R.sup.8 is joined with R.sup.1 to form --CH.sub.2 --; and the salts, hydrates, tautomers and solvates thereof. 3. The compound of claim 2 wherein R.sup.2 is --H. 4. The compound of claim 3 wherein R.sup.1 is --CH.sub.3. 5. The compound of claim 1 wherein R.sup.2 is --H. 6. The compound of claim 1 wherein one R.sup.2 is --CH.sub.3 and the other R.sup.2 is H. 7. The compound of claim 1 wherein R.sup.3 is C.sub.1 -C.sub.6 alkyl or phenyl. 8. The compound of claim 1 wherein R.sup.3 is --CH.sub.3 or --C.sub.2 H.sub.5. 9. The compound of claim 1 wherein X is O. 10. The compound of claim 1 wherein X is N and one R.sup.3 is H. 11. The compound of claim 4 wherein the compound is enriched or resolved at the carbon atom chiral center linked to R.sup.1. 12. The compound of claim 4 wherein at least about 90% of the compound is in the (R) configuration at the R.sup.1 site. 13. The compound of claim 12 wherein B is adenin-9-yl. 14. The compound of claim 13 wherein each R is ethyl. 15. The compound of claim 13 wherein each R is isopropyl. 16. The compound of claim 13 wherein each R is 3-pentyl or neopentyl. 17. The compound of claim 13 wherein each R is t-butyl or isobutyl. 18. The compound of claim 4 wherein B is 2,6-diaminopurin-9-yl. 19. The compound of claim 3 wherein R.sup.1 is H. 20. The compound of claim 19 wherein B is adenin-9-yl. 21. The compound of claim 4 wherein R is C.sub.1 -C.sub.12 alkyl. 22. The compound of claim 3 wherein R.sup.1 is --CH.sub.2 OH. 23. The compound of claim 22 wherein B is cytosin-1-yl. 24. The compound of claim 22 wherein at least about 90% of the compound is in the (S) configuration at the R.sup.1 site. 25. A method comprising orally administering to a patient infected with virus or at risk to viral infection a therapeutically effective amount of a compound of claim 1. 26. A method for preparing a compound of formula (1a) of claim 1 comprising reacting the diacid of a phosphonomethoxy nucleotide analog with L--CH(R.sup.2)OC(O)X(R).sub.n wherein L is a leaving group. 27. A method for preparing a compound of formula (1) of claim 2 comprising reacting a compound of formula (6) ##STR35## with L--CHR.sup.2 --O--C(O)--OR and recovering a compound of formula (1), wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl; R.sup.1 is hydrogen, --CH.sub.3, --CH.sub.2 OH, --CH.sub.2 F, --CH.dbd.CH.sub.2, --CH.sub.2 N.sub.3 or R.sup.1 and R.sup.8 are joined to form --CH.sub.2 --; and R.sup.8 is hydrogen, --CHR.sup.2 --O--C(O)--OR or R.sup.8 is joined with R.sup.1 to form --CH.sub.2 --; and R.sup.2 is H, C.sub.1 -C.sub.12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR.sup.3 in which R.sup.3 is C.sub.1 -C12 alkyl; R is independently H, C.sub.1 -C.sub.12 alkyl, aryl, alkenyl, alkynyl, alkenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR.sup.3, provided that at least one R is not H; and L is a leaving group. 28. The method of claim 27 comprising conducting the reaction using at least about 1.0 equivalent of L--CHR.sup.2 --O--C(O)--OR. 29. The method of claim 27 comprising conducting the reaction in the presence of an organic base in an organic solvent at a reaction temperature of about 4-100.degree. C. for about 4-72 hours. 30. The method of claim 27 wherein the compound of formula (1) is recovered by forming a salt, precipitating the salt and recovering the precipitated salt. 31. The method of claim 30 wherein the salt is formed from sulfuric acid, phosphoric acid, lactic acid, or citric acid.