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Last Updated: March 28, 2024

Claims for Patent: 8,759,318


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Summary for Patent: 8,759,318
Title:Phosphoramidate derivatives of guanosine nucleoside compounds for treatment of viral infections
Abstract: Phosphoramidate compounds derived from guanine bases having enhanced therapeutic potency are provided, and these compounds in particular have enhanced potency with respect to treatment of viral infections, such as hepatitis C virus. Pharmaceutical compositions, methods of preparing the compounds, and methods of using the compounds and compositions to treat viral infections are also provided.
Inventor(s): Chamberlain; Stanley (Alpharetta, GA), Hutchins; Jeff (Alpharetta, GA), Madela; Karolina (Cardiff, GB), McGuigan; Christopher (Cardiff, GB), Vernachio; John (Alpharetta, GA), Aljarah; Mohamed (Cardiff, GB), Gilles; Arnaud (Cardiff, GB)
Assignee: Inhibitex, Inc. (Alpharetta, GA) University College Cardiff Consultants Limited (Cardiff, GB)
Application Number:13/143,098
Patent Claims:1. A compound of formula (I) below having the structure: ##STR00298## wherein Ar is selected from naphthyl, ##STR00299## any of which are optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, di(C.sub.1-C.sub.6)alkylamino or C.sub.1-C.sub.6alkylcarboxy(C.sub.1-C.sub.6)alkyl-; X is selected from S, NH and O; R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, benzyl, substituted benzyl; and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.2 is selected from hydrogen, phenyl, aryl, and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.3 is selected from H and OH; R.sup.4 and R.sup.5 are independently selected from hydrogen, C.sub.1-C.sub.6alkyl optionally substituted with alkylthio, benzyl optionally substituted with one or more halo, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkoxy, phenyl optionally substituted with one or more halo, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkoxy; R.sup.6 is selected from C.sub.1-C.sub.10alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl-alkyl-, phenyl(C.sub.1-C.sub.6)alkyl- optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, and halo, indanyl and heterocycloalkyl; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein the compound is in the form of a polymorph.

3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.

4. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable carrier is pure sterile water, phosphate buffered saline or an aqueous glucose solution.

5. The compound of claim 1 wherein Ar is selected from: naphthyl, ##STR00300## any of which are optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, di(C.sub.1-C.sub.6)alkylamino; or C.sub.1-C.sub.6alkylcarboxy(C.sub.1-C.sub.6)alkyl-.

6. The compound of claim 1 wherein X is O.

7. The compound of claim 1 wherein R1 is C1-C6 alkyl.

8. The compound of claim 1 wherein R2 is hydrogen.

9. The compound of claim 1 wherein R3 is OH.

10. The compound of claim 1 wherein R.sup.4 and R.sup.5 are independently selected from hydrogen, C.sub.1-C.sub.6alkyl optionally substituted with alkylthio, and phenyl optionally substituted with one or more halo, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkoxy.

11. The compound of claim 1 wherein R.sup.4 is selected from C.sub.1-C.sub.6alkyl optionally substituted with alkylthio, and phenyl optionally substituted with one or more halo, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkoxy; and R.sup.5 is hydrogen.

12. The compound of claim 1 wherein R.sup.6 is selected from C.sub.1-C.sub.10alkyl, phenyl(C.sub.1-C.sub.6)alkyl- optionally substituted with halo.

13. A compound selected from the group consisting of the following formulas: ##STR00301## and pharmaceutically acceptable salts thereof.

14. A method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprising administering to a mammal in need thereof an effective amount of the compound of claim 1.

15. The method according to claim 14, wherein said virus is hepatitis C virus.

16. A method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprising administering to a mammal in need thereof an effective amount of the pharmaceutical composition of claim 3.

17. The method according to claim 16, wherein said virus is hepatitis C virus.

18. A method for treating a hepatitis C viral infection in a mammal comprising administering to a mammal in need thereof an effective amount of the compound of claim 1.

19. The method according to claim 18 wherein the compound is administered in combination with a therapeutically effective amount of one or more agents active against hepatitis C virus.

20. The method of claim 19 wherein said agent active against hepatitis C virus is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin.

21. The method of claim 19 wherein said agent active against hepatitis C virus is selected from the group consisting of ribavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of HCV NS3 serine protease, interferon-.alpha., pegylated interferon-.alpha. (peginterferon-.alpha.), and combinations thereof.

22. The method of claim 21 wherein interferon-.alpha. is selected from the group consisting of recombinant interferon-.alpha.2a, interferon-.alpha.2b, a consensus interferon, and a purified interferon-.alpha. product.

23. The method of claim 19 wherein said agent active against hepatitis C virus is an agent that inhibits a material selected from the group consisting of HCV proteases, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and inosine 5'-monophosphate dehydrogenase.

24. The method of claim 19 wherein said agent active against hepatitis C virus is a nucleoside analog for the treatment of an HCV infection.

25. The method of claim 19 wherein said agent active against hepatitis C virus is selected from the group consisting of Omega IFN, BILN-2061, Roferon A, Pegasys, Pegasys/Ribaravin, CellCept, Wellferon, Albuferon-.alpha., Levovirin, IDN-6556, IP-501, Actimmune, Infergen A, ISIS 14803, JTK-003, Pegasys/Ceplene, Ceplene, Civacir, Intron A/Zadaxin, Levovirin, Viramidine, Heptazyme, Intron A, PEG-Intron, Rebetron, Ribavirin, PEG-Intron/Ribavirin, Zadazim, Rebif, IFN-.beta./EMZ701, T67, VX-497, VX-950/LY-5703 10, Omniferon, XTL-002, SCH 503034, isatoribine and its prodrugs ANA971 and ANA975, R1479, Valopicitabine, NIM811, and Actilon.

26. A method for treating a hepatitis C viral infection in a mammal comprising administering to a mammal in need thereof an effective amount of the pharmaceutical composition of claim 3.

27. The method according to claim 26 wherein the composition is administered in combination with a therapeutically effective amount of one or more agents active against hepatitis C virus.

28. A method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprising administering to a mammal in need thereof an effective amount of the compound of claim 13.

29. The method according to claim 28, wherein said virus is hepatitis C virus.

30. A method for treating a hepatitis C viral infection in a mammal comprising administering to a mammal in need thereof an effective amount of the compound of claim 13.

31. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier, excipient or diluent.

32. A method for treating a hepatitis C viral infection in a mammal comprising administering to a mammal in need thereof an effective amount of the composition of claim 31.

33. The compound according to claim 1 wherein the compound includes different diastereomers around phosphorous in formula I.

34. The compound according to claim 33 wherein the compound includes a mixture of two phosphorous diastereomers in any proportion from 1:99 to 99:1.

35. A method of separating the phosphorous diastereomers of the compound of claim 34 comprising conducting a chiral chromatographic step performed on a chiral resin.

36. The compound according to claim 1 wherein the compound has a specific formula selected from the group consisting of the following: ##STR00302## ##STR00303## ##STR00304## and phosphorus diastereomers thereof.

37. The compound according to claim 1 wherein the compound is selected from the group consisting of the following: Benzyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)pr- opanoate; 1(S)-Phenylethyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl) -3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)p- hosphorylamino)propanoate; 2,2-Dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl) -3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy) phosphorylamino)propanoate; (2S)-Tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin -9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-y- loxy)phosphorylamino)propanoate; (2S)-Methyl 2-(6-((((2R, 3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahyd- rofuran-2-yl(methoxy)((S)- 1 -(neopentyloxy)- 1 -oxopropan-2-ylamino)phosphoryloxy)naphthalen-2-yl)propanoate; 2,4-Difluorobenzyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl) -3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy) phosphorylamino)-3 -methylbutanoate; (2S)-2,4-Difluorobenzyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)-3-methylb- utanoate; (2S)-Neopentyl 2-(((((2R,-3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-met- hyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-4-(me- thylthio)butanoate; (2S)-Benzyl 2-(((((2R,-3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-met- hyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phe- nylacetate; (2S)-Neopentyl 2-(((((2R,-3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-met- hyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phe- nylacetate; 2,2-Dimethylpropyl 2(S)-((((2R,3R,4R,5R)- 5-(2-amino-6-ethoxy-9H-purin-9-yl) -3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)p- hosphorylamino)propanoate; 1(S)-Phenylethyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl) -3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)p- hosphorylamino)propanoate; 2,2-Dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)pr- opanoate; Benzyl 2(S)-((((2R,-3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-- 4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)p- ropanoate; (2S)-2,4-Difluorobenzyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoa- te; 1(S)-Phenylethyl 2(S)-((((2R,-3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-- 4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)p- ropanoate; (2S)-2,3-Dihydro-1H-inden-2-yl 2-((((2R,-3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propano- ate; (2S)-Propyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoa- te; (2S)-3,3-Dimethylbutyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoa- te; (2S)-Isobutyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoa- te; 2,2-Dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)pr- opanoate; (S)-P 2,2-Dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy(naphthalene- 1 -yloxy) phosphorylamino)propanoate; (R)-P 2,2-Dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)pr- opanoate; (2S)-Isopropyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoa- te; (2S)-Cyclopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoa- te; (2S)-Cyclohexyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoa- te; (2S)-Tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoa- te; (2S)-2,4-difluorobenzyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl-3,4-dihydroxy-4-methyl- tetrahydrofuran-2-yl)methoxy)(6-((S)-1 -methoxy-1-oxopropan-2-yl)naphthalen-2-yloxy)phosphorylamino)propanoate; (2S)-methyl 2-(6-((((2R, 3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahyd- rofuran-2-yl)methoxy)((,S)-1-(neopentyloxy)-1-oxopropan-2-ylamino)phosphor- yloxy)naphthalen-2-yl)propanoate; (2S)-methyl2-(6-((((2R, 3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahyd- rofuran-2-yl)methoxy)((S)-1-oxo-1-(tetrahydro-2H-pyran-4-yloxy)propan-2-yl- amino)phosphoryloxy)naphthalen-2-yl)propanoate; (2S)-2,4-difluorobenzyl 2-((((2R, 3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yemethoxy)(quinolin-5-yloxy)phosphorylamino)propanoate- ; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(quinolin-5-yloxy)phosphorylamino)propanoate- , (2S)-tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(quinolin-5-yloxy)phosphorylamino)propanoate- ; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)propanoate- ; (2S)-tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl(methoxy)(quinolin-6-yloxy)phosphorylamino)propanoate- ; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; (2S)-Neopentyl 2((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyl- tetrahydrofuran-2-yl)methoxy)(6-((S)-1-methoxy-1-oxopropan-2-yl1)naphthale- n-2-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-2,4-Difluorobenzyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(quinolin-5-yloxy)phosphorylamino)-3-methylb- utanoate; (2S)-Neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(quinolin-5-yloxy)phosphorylamino)-3-methylb- utanoate; (2S)-2,4-Difluorobenzyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)-3-methylb- utanoate; (2S)-Neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)-3-methylb- utanoate; (2S)-Neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3 ,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-8-yloxy)phosp- horylamino)-3-methylbutanoate; (2S)-Neopentyl 2-((((2R,3R,4R))-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(2-methylnaphthalen-1-yloxy)phosphorylamino- )-3-methylbutanoate; (2S)-Neopentyl 2-(((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(3-tert-butylnaphthalen--yloxy)phosphorylam- ino)-3-methylbutanoate; (2S)-Neopentyl 2-(((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(3,7-di-tert-butylnaphthalen-1-yloxy)phosph- orylamino)-3-methylbutanoate; Benzyl 2(S)-((((2R,3R,4R, 5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrof- uran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)-3-methylbutanoate; 2,4-Difluorobenzyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)-3 -methylbutanoate; (2)-((S)-1-Phenylethyl) 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methy- lbutanoate; (2S)-((S)-1-(4-BromophenyDethyl) 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methy- lbutanoate; (2S)-((S)-1-(2-Bromophenyl)ethyl) 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methy- lbutanoate; (2S)-Methyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methy- lbutanoate; (2S)-Neopentyl 2-((((2R,-3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-meth- ylbutanoate; (2S)-Cyclopropylmethyl 2-((((2R,-3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-meth- ylbutanoate; (2S)-Cyclobutyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methy- lbutanoate; Cyclopentyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)-3- -methylbutanoate; Cyclohexyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)-3- -methylbutanoate; (2S)-Tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methy- lbutanoate; (2S)-benzyl 2-(((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phen- ylacetate; (2S)-methyl 2-(((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phen- ylacetate; (2S)-propyl 2-(((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phen- ylacetate; (2S)-neopentyl 2-(((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-meth- yltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phen- ylacetate; (2S)-cyclohexyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methy- ltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-pheny- lacetate; (2S)-benzyl 2-((((2R,3R,4R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyl- tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoat- e; (2S)-2,4-difluorobenzyl 2-((((2R,3R,4R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyl- tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoat- e; (2S)-((S)-1-phenylethyl) 2-((((2R, 3R,4R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydr- ofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; 2,2-dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-3,4-dihydroxy-4-- methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)pro- panoate; (2S)-isopropyl 2-((((2R,3R,4R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyl- tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoat- e; (2S)-tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyl- tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoat- e; (2S)-neopentyl 2-((((2R, 3R,4R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydr- ofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate- ; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)pr- opanoate; (2S)-((S)-1-phenylethyl) 2-((((2R,3R,4R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3,4-dihydroxy-4- -methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)pr- opanoate; (2S)-neopentyl 2-4((((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3,4-dihydro- xy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)- propanoate; 2,2-Dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-benzylamino-9H-purin-9-yl)-3,4-dihydro- xy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamin- o)propionate; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-(phenethylamino)-9H-purin-9-yl)-3,4-dihydrox- y-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino- )propanoate; (2S)-((S)-1-phenylethyl) 2-((((2R,3R,4R)-5-(2-amino-6-(methylthio)-9H-purin-9-yl)-3,4-dihydroxy-4-- methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)pro- panoate; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-(methylthio)-9H-purin-9-yl)-3,4-dihydroxy-4-- methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)pro- panoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-6-(methylthio)-9H-purin-9-yl)-3,4-dihydroxy- -4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)pr- opanoate; (2S)-benzyl 2-((((2S,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-hydroxy-4-methyltetrah- ydrofuran-2-yemethoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-((S)-1-phenylethyl) 2-((((2S,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-hydroxy-4-methyltetrah- ydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2S,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-hydroxy-4-methyltetrah- ydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-cyclohexyl 2-((((2S,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-hydroxy-4-methyltetrah- ydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; benzyl (2S)-benzyl 2-((((2S,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-hydroxy-4-methyltetrah- ydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutano- ate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-(4-fluorobenzylamino)-6-methoxy-9H-purin-9-yl)-3,-

4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy) (naphthalen-1-yloxy)phosphorylamino)propanoate; and phosphorus diastereomers thereof.

38. A pharmaceutical composition comprising a liquid oral formulation of a compound according to claim 1.

39. The composition according to claim 38 wherein the formulation comprises DMA/PEG 400/Solutol HS 15/sodium acetate pH 4.0 and Capmul/Tween 80; SEDDS-4; MLM; SE-21.

40. A compound selected from the group consisting of the following: (3R,4R,5R)-2-(2-amino-6-ethoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methylt- etrahydrofuran-3,4-diol; (3R,4R,5R)-2-(2-amino-6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-3-- methyltetrahydrofuran-3,4-diol; (3R,4R,5R)-2-(2-amino-6-(phenethylamino)-9H-purin -9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol; (2R,3R,4R, 5R)-2-(2-(4-fluorobenzylamino)-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)- -3-methyltetrahydrofuran-3,4-diol; and (3R,5S)-2-(2-amino-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyl-te- trahydrofuran-3-ol.

41. A compound of formula (XL) below having the structure: ##STR00305## wherein X, is selected from S, NH and O; R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, benzyl, substituted benzyl; and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.2 is selected from hydrogen, phenyl, aryl, and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.3 is selected from H and OH; R.sup.4 and R.sup.5 are independently selected from hydrogen, C.sub.1-C.sub.6alkyl optionally substituted with alkylthio, benzyl optionally substituted with one or more halo, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkoxy, phenyl optionally substituted with one or more halo, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkoxy; and R.sup.6 is selected from C.sub.1-C.sub.10alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl-alkyl-, phenyl(C.sub.1-C.sub.6)alkyl- optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, and halo, indanyl and heterocycloalkyl; and pharmaceutically acceptable salts thereof.

42. The compound of claim 41 wherein R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl,30 (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

43. A compound of formula (XLI) below having the structure: ##STR00306## wherein Ar is selected from naphthyl, ##STR00307## any of which are optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, di(C.sub.1-C.sub.6)alkylamino or C.sub.1-C.sub.6alkylcarboxy(C.sub.1-C.sub.6)alkyl-; X is selected from S, NH and O; R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, benzyl, substituted benzyl; and aryl(C.sub.O-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.2 is selected from hydrogen, phenyl, aryl, and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.3 is selected from H and OH; R.sup.6 is selected from C.sub.1-C.sub.10alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl-alkyl-, phenyl(C.sub.1-C.sub.6)alkyl- optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, and halo, indanyl and heterocycloalkyl; and pharmaceutically acceptable salts thereof.

44. The compound of claim 43 wherein Ar is selected from (S)-2-(3-methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin-8 yl.

45. The compound of claim 43 wherein Ar is selected from (S)-2-(3-methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin 8-yl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

46. The compound of claim 43 wherein X.dbd.O, R.sup.1=Me, R.sup.2.dbd.H, and R.sup.3.dbd.OH.

47. A compound of formula (XLII) below having the structure: ##STR00308## wherein Ar is selected from naphthyl, ##STR00309## any of which are optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, di(C.sub.1-C.sub.6)alkylamino or C.sub.1-C.sub.6alkylcarboxy(C.sub.1-C.sub.6)alkyl-; X is selected from S, NH and O; R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, benzyl, substituted benzyl; and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.2 is selected from hydrogen, phenyl, aryl, and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.3 is selected from H and OH; and R.sup.6 is selected from C.sub.1-C.sub.10alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl-alkyl-, phenyl(C.sub.1-C.sub.6)alkyl- optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, and halo, indanyl and heterocycloalkyl; and pharmaceutically acceptable salts thereof.

48. The compound of claim 47 wherein Ar is selected from (S)-2-(3-methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin 8 yl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

49. The compound of claim 47 wherein Ar is 1-naphthyl.

50. The compound of claim 47 wherein Ar is 1-naphthyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

51. The compound of claim 47 wherein X.dbd.O, R.sup.1=Me, R.sup.2.dbd.H, and R.sup.3.dbd.OH.

52. A compound of formula (XLIII) below having the structure: ##STR00310## wherein Ar is selected from naphthyl, ##STR00311## any of which are optionally substituted with C.sub.1-C.sub.6alkoxy, di(C.sub.1-C.sub.6)alkylamino or C.sub.1-C.sub.6alkylcarboxy(C.sub.1-C.sub.6)alkyl-; X is selected from S, NH and O; R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, benzyl, substituted benzyl; and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.2 is selected from hydrogen, phenyl, aryl, and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.3 is selected from H and OH; and R.sup.6 is selected from C.sub.1-C.sub.10alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl-alkyl-, phenyl(C.sub.1-C.sub.6)alkyl- optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, and halo, indanyl and heterocycloalkyl; and pharmaceutically acceptable salts thereof.

53. The compound of claim 52 wherein Ar is selected from (S)-2-(3-methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin 8 yl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3 -dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

54. The compound of claim 52 wherein wherein Ar is 1-naphthyl.

55. The compound of claim 52 wherein wherein Ar is 1-naphthyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

56. The compound of claim 52 wherein X.dbd.O, R.sup.1=Me, R.sup.2.dbd.H, and R.sup.3.dbd.OH.

57. The compound of claim 1 wherein X.dbd.O.

58. The compound of claim 57 wherein R.sup.4 and R.sup.5 are independently selected from hydrogen, methyl, isopropyl, 2-thiomethylethyl, 2-methylpropyl, 1-methylpropyl, and phenyl.

59. The compound of claim 57 wherein R.sup.1 is ethyl.

60. The compound of claim 57 wherein R.sup.1 is ethyl; Ar is selected from (S)-2-(3-methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin 8yl; R.sup.4 and R.sup.5 are independently selected from methyl, isopropyl, 2-thiomethylethyl, 2-methylpropyl, 1-methylpropyl,and phenyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

61. The compound of claim 57 wherein R.sup.2.dbd.H, and R.sup.3 .dbd.OH.

62. The compound of claim 1 wherein X=NH.

63. The compound of claim 62 wherein Ar is selected from (S)-2-(3-methoxybut-3 -oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin-8-yl; R.sup.4 and R.sup.5 are independently selected from hydrogen, methyl, isopropyl, 2-thiomethylethyl, 2-methylpropyl, 1-methylpropyl, and phenyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

64. The compound of claim 62 wherein R.sup.2.dbd.H, and R.sup.3.dbd.OH.

65. The compound of claim 1 wherein X.dbd.S.

66. The compound of claim 65 wherein Ar is selected from (S)-2-(3-methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3 ,7-di-tert-butylnaphthalen- 1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin-8-yl, R.sup.4 and R.sup.5 are independently selected from hydrogen, methyl, isopropyl, 2-thiomethylethyl, 2-methylpropyl, 1-methylpropyl, and phenyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

67. The compound of claim 65 wherein R.sup.1=Me, R.sup.2.dbd.H, and R.sup.3.dbd.OH.

68. The compound of claim 1 wherein R.sup.3 is H.

69. The compound of claim 68 wherein X is O.

70. The compound of claim 68 wherein Ar is selected from (S)-2-(3-rnethoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tent-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin-8-yl R.sup.1 is methyl; R.sup.4 and R.sup.5 are independently selected from hydrogen, methyl, isopropyl, 2-thiomethylethyl, 2-methylpropyl, 1-methylpropyl, and phenyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

71. The compound of claim 68 wherein Ar is selected from (S)-2-(3-methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tent-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin-8-yl; X is O; R.sup.4 and R.sup.5 are independently selected from hydrogen, methyl, isopropyl, 2-thiomethylethyl, 2-methylpropyl, 1-methylpropyl, and phenyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo) benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

72. The compound of claim 68 wherein Ar is selected from (S)-2-(3 -methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin-8yl X is O; R.sup.1 is methyl; R.sup.4 and R.sup.5 are independently selected from hydrogen, methyl, isopropyl, 2-thiomethylethyl, 2-methylpropyl, 1-methylpropyl, and phenyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

73. The compound of claim 68 wherein R.sup.2.dbd.H.

74. The compound of claim 1 wherein X.dbd.O and wherein R.sup.2 is other than H.

75. The compound of claim 74 wherein Ar is selected from (S)-2-(3 -methoxybut-3-oxo-2-yl)naphthalen-6-yl, 2-methylnaphthalen-1-yl, 3-tert-butylnaphthalen-1-yl, 3,7-di-tert-butylnaphthalen-1-yl, 1-naphthyl, 2-naphthyl, quinolin-5-yl, quinolin-6-yl, and quinolin-8-yl, R.sup.1 is methyl; R.sup.2 is other than H; R.sup.4 and R.sup.5 are independently selected from hydrogen, methyl, isopropyl, 2-thiomethylethyl, 2-methylpropyl, 1-methylpropyl, and phenyl; and R.sup.6 is selected from benzyl, (S)-1-(2-bromo)benzyl, 2,4-difluorobenzyl, (S)-1-phenylethyl, (S)-1-(4-bromophenyl)ethyl, (S)-1-(2-bromophenyl)ethyl, 2,3-dihydro-1H-inden-2-yl, methyl, n-propyl, 3,3-dimethyl butyl, 2-methylpropyl, 2,2-dimethylpropyl, isopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyran-4-yl.

76. The compound of claim 74 wherein R.sup.3.dbd.OH.

77. The method of claim 35 wherein the chiral resin is selected from the group consisting of CHIRALPAK.RTM. IA.TM., CHIRALPAK.RTM. IA-3, CHIRALPAK.RTM. AD-H, CHIRALPAK.RTM. AD, CHIRALPAK.RTM. AD-3, CHIRALPAK.RTM. AD-3R, CHIRALPAK.RTM. AS-H, CHIRALPAK.RTM. AS, CHIRALPAK.RTM. AY-H, CHIRALPAK.RTM. AY, CHIRALPAK.RTM. AZ-H, CHIRALPAK.RTM. AZ, CHIRALPAK.RTM. IB.TM., CHIRALCEL.RTM. OD-H, CHIRALCEL.RTM. OD, CHIRALCEL.RTM. OD-3, CHIRALCEL.RTM. OD-3R, CHIRALCEL.RTM. OD-I, CHIRALPAK.RTM. IC.TM., CHIRALPAK.RTM. IC-3, CHIRALCEL.RTM. OC-H, CHIRALCEL.RTM. OC, CHIRALCEL.RTM. OA, CHIRALCEL.RTM. OB-H, CHIRALCEL.RTM. OB, CHIRALCEL.RTM. OG, CHIRALCEL.RTM. OJ-H, CHIRALCEL.RTM. OJ, CHIRALCEL.RTM. OF, CHIRALCEL.RTM. OK, CHIRALCEL.RTM. OZ-H, and CHIRALCEL.RTM. OZ.

78. A compound of formula (I) below having the structure: ##STR00312## wherein Ar is selected from phenyl, naphthyl, ##STR00313## any of which are optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, di(C.sub.1-C.sub.6)alkylamino or C.sub.1-C.sub.6alkylcarboxy(C.sub.1-C.sub.6)alkyl-; X is selected from S, NH and O; R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, benzyl, substituted benzyl; and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.2 is selected from hydrogen, phenyl, aryl, and aryl(C.sub.0-C.sub.6)alkyl- wherein the aryl is optionally substituted by halo, C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; R.sup.3 is selected from H and OH; R.sup.4and .sup.5 are independently selected from hydrogen, C.sub.1-C.sub.6alkyl optionally substituted with alkylthio, benzyl optionally substituted with one or more halo, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkoxy, phenyl optionally substituted with one or more halo, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkoxy; R.sup.6 is selected from C.sub.1-C.sub.10alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl-alkyl-, phenyl(C.sub.1-C.sub.6)alkyl- optionally substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, and halo, indanyl and heterocycloalkyl; and pharmaceutically acceptable salts thereof, wherein n the compound is in the form of a polymorph.

Details for Patent 8,759,318

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 06/04/1986 ⤷  Try a Trial 2029-01-09
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 ⤷  Try a Trial 2029-01-09
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b Injection 103132 ⤷  Try a Trial 2029-01-09
Kadmon Pharmaceuticals Llc INFERGEN interferon alfacon-1 Injection 103663 10/06/1997 ⤷  Try a Trial 2029-01-09
Emd Serono, Inc. REBIF interferon beta-1a Injection 103780 03/07/2002 ⤷  Try a Trial 2029-01-09
Emd Serono, Inc. REBIF interferon beta-1a Injection 103780 12/17/2004 ⤷  Try a Trial 2029-01-09
Emd Serono, Inc. REBIF interferon beta-1a Injection 103780 12/21/2012 ⤷  Try a Trial 2029-01-09
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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