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1. WO1992018517 - PROCEDE DE TRAITEMENT OU DE PREVENTION DU VIRUS DE L'HEPATITE B

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

What Is Claimed Is:

1. (-)3'-Thia-2',3'-dideoxycytidine of the following formula:


2. (-)5-Fluoro-3'-thia-2',3'-dideoxycytidine of the following formula:

3. A method of treating a patient suffering from hepatitis B virus or preventing hepatitis B virus infection comprising administering to said patient an effective amount of an active compound selected from the group consisting of (a) a compound having the formula (I)


wherein R is H or F, and (b) ß-dioxolane-cytosine, or a salt of said active compound or an ester of said active compound, either alone or in admixture within a diluent.

4. The method of claim 3, wherein said active compound is the compound of formula (I) and is in admixture with a compound of the following formula (I"):


wherein R is H or F, or a salt or ester thereof either alone or in admixture with a diluent.

5. The method of claim 4, wherein R is H.

6. The method of claim 4, wherein R is F.

7. The method of claim 3, wherein the active compound is (-)3'-thia-2',3'-dideoxycytidine of the formula



8. The method of claim 3, wherein the active compound is (-)5-fluoro-3'-thia-2',3'-dideoxycytidine of the formula


9. The method of claim 3, wherein the active compound is (-)L-ß-dioxolane-cytosine.

10. The method of claim 3, wherein an ester of said active compound is administered.

11. The method of claim 7, wherein an ester of said active compound is administered.

12. The method of claim 8, wherein an ester of said active compound is administered.

13. The method of claim 3, wherein said active compound is administered in a dose of 1 to 100 mg/kg of body weight per day and said patient is a human.

14. The method of claim 3, wherein said active compound of formula is administered in a dose of 2 to 50 mg/kg of body weight per day and said patient is a human.

15. The method of claim 3, wherein said active compound is administered in a dose of 2 to 10 mg/kg of body weight per day and said patient is a human.

16. The method of claim 7 , wherein said active compound is administered in a dose of 1 to 100 mg/kg of body weight per day and said patient is a human.

17. The method of claim 7, wherein said active compound is administered in a dose of 2 to 50 mg/kg of body weight per day and said patient is a human.

18. The method of claim 7, wherein said active compound is administered in a dose of 2 to 10 mg/kg of body weight per day and said patient is a human.

19. The method of claim 8, wherein said active compound is administered in a dose of 1 to 100 mg/kg of body weight per day and said patient is a human.

20. The method of claim 8, wherein said active compound is administered in a dose of 2 to 50 mg/kg of body weight per day and said patient is a human.

21. The method of claim 8, wherein said active compound is administered in a dose of 2 to 10 mg/kg of body weight per day and said patient is a human.

22. The method of claim 4, wherein said compound of formula (I") is administered in a dose of 1 to 100 mg/kg of body weight per day and said patient is a human.

23. The method of claim 4, wherein said compound of formula (I") is administered in a dose of 2 to 50 mg/kg of body weight per day and said patient is a human.

24. The method of claim 4, wherein said compound of formula (I") is administered in a dose of 2 to 10 mg/kg of body weight per day and said patient is a human.

25. The method of claim 3, wherein said active compound is administered in combination with an anti-viral effective amount of adenine arabinoside or interferon α.

26. A method for preparing (-)3'-thia-2',3'-dideoxycytidine according to claim 1 comprising contacting

(±)3'-thia-2',3'-dideoxycytidine with deoxycytidine deaminase, subjecting the resultant mixture to column chromatography and separating out said (-)3'-thia-2',3'-dideoxycytidine.

27. The method of claim 24, wherein the column chromatography is HPLC.

28. A method for preparing (-)5-fluoro-3'-thia-2',3'- dideoxycytidine according to claim 2 comprising contacting (±)5-fluoro-3'-thia-2',3'-dideoxycytidine with deoxycytidine deaminase, subjecting the resultant mixture to column chromatography and separating out said (-)5-fluoro-3'-thia- 2',3'-dideoxycytidine.

29. The method of claim 26, wherein the column
chromatography is HPLC.

30. The method of claim 28, wherein said contacting is carried out at a temperature of 37ºC for 16 hours.

31. The method of claim 29, wherein said contacting is carried out at a temperature of 37ºC for 16 hours.

32. (±)ß-Dioxolane-cytosine.

33. (-)-L-ß-Dioxolane-cytosine.

34. A compound of the formula


wherein Bz is a benzoyl group and Ac is an acetyl group.

35. A method of producing an L-isomer of a dioxolane nucleoside analog comprising (a) contacting L-gulose with an acid,

(b) oxidizing and then reducing the product from step (a) without selective protective to form a dioxolane triol having two adjacent hydroxyl groups,

(c) contacting the dioxolane triol from step (b) with protecting groups to selectively protect the two adjacent hydroxyl groups to form an isopropylidene compound,

(d) contacting the isopropylidene compound from step (c) with a benzoylating group and then conducting hydrolysis,

(e) oxidizing the product from step (d),

(f) subjecting the product from step (e) to an oxidative decarboxylation to form an acetate,

(g) contacting the product (f) with a silylated base and

(h) conducting debenzoylation on the product from
step (g).

36. The method of claim 35, wherein in step (a), L-glucose is contacted with HCl at a temperature of 100ºC; in step (b), the oxidation is carried out with NaIO4 and the reduction is carried out with NaBH4; in step (c) the protecting group is provided by p-toluene sulfonyl; in step (d), the benzoylating group is provided by benzoylchloride and the hydrolysis is carried out with sulfonyl p-toluene; in step (e) the oxidation is carried out with NaIO4 and RuO2; in step (f), the oxidative decarboxylation is carried out with Pb(OAc)4 and in step (g) the silylated base is trimethylsilyltriflate.