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Claims for Patent: 5,922,695

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Claims 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(R.sup.2).sub.2 OC(O)X(R).sub.a, wherein R.sup.2 independently 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; X is N or O; R is independently 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, --O--, --N.dbd., --NR.sup.4 --, --N(R.sup.4).sub.2 -- or OR.sup.3, 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 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 OR.sup.3. 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): Arimilli; Murty N. (Fremont, CA), Cundy; Kenneth C. (Belmont, CA), Dougherty; Joseph P. (New York, NY), Kim; Choung U. (San Carlos, CA), Oliyai; Reza (Foster City, CA), Stella; Valentino J. (Lawrence, KS)
Assignee: Gilead Sciences, Inc. (Foster City, CA)
Application Number:08/900,746
Patent Claims: 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.
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